Résumé
Background Antidepressant drugs are used as first-line treatment in depression, but response has been shown to be highly heterogeneous, with drugs often failing to have the desired therapeutic effect. We report on an integrative analysis from the Genome-Based Therapeutic Drugs for Depression (GENDEP) study using gene expression from mice to inform prioritization in a human pharmacogenetic study. Methods The same two antidepressants were used in mice and humans: escitalopram (a serotonin reuptake inhibitor) and nortriptyline (a norepinephrine reuptake inhibitor). The animal study used four inbred strains of mice (129S1/SvlmJ, C57LB/6J, DBA/2J, and FVB/NJ). Hippocampus mRNA levels were measured in 144 animals using the Affymetrix MOE 430 v2 chip. Results Based on gene-expression analysis of strain-by-drug interactions, 17 genes differentially expressed with nortriptyline or escitalopram versus saline were prioritized in the human pharmacogenetic analysis. Single nucleotide polymorphisms tagging common sequence variation in human orthologs of these genes were tested for association with response to antidepressants in 706 participants of the GENDEP human pharmacogenetic study, treated with escitalopram or nortriptyline for 12 weeks, with available high-quality Illumina 610 quad array genotyping. Several polymorphisms in the protein phosphatase 1A gene (PPM1A) remained significantly associated with response to nortriptyline in humans after correction for multiple comparisons within the gene. PPM1A encodes a phosphatase involved in mitogen-activated protein kinase signaling and cell stress response. Conclusions Convergent evidence from mice and humans suggests a role of the PPM1A in response to noradrenergic but not serotonergic antidepressants.
| Langue d'origine | English |
|---|---|
| Pages (de-à) | 360-365 |
| Nombre de pages | 6 |
| Journal | Biological Psychiatry |
| Volume | 69 |
| Numéro de publication | 4 |
| DOI | |
| Statut de publication | Published - févr. 15 2011 |
| Publié à l'externe | Oui |
Note bibliographique
Funding Information:Using a novel strategy with matching animal and human experiments, we have obtained convergent evidence suggesting a role of a previously unexplored gene ( PPM1A ) in determining individual differences in treatment outcome with the noradrenergic antidepressant nortriptyline. Specifically, the mRNA probe sets showed the largest change in PPM1A expression with nortriptyline treatment in the hippocampus of the mouse strain that also showed the strongest effects of nortriptyline on behavioral tests. The strain-dependent regulation of the PPM1A gene in response to drug treatment is presented in the Supplement 1 (Figure S1) , where it can be observed that the interaction effect largely comes from strain DBA differing from the others strains. Multiple markers within human PPM1A predicted clinical response to nortriptyline among patients with major depression. These pharmacogenetic associations remained significant after correction for the number of markers within PPM1A and had high posterior probability of being genuine associations after taking into account the multiple comparisons across prioritized genes. Both mouse and human studies found the involvement of PPM1A to be specific to nortriptyline but not escitalopram. PPM1A is a functionally plausible candidate gene for antidepressant pharmacogenetics because it is strongly expressed in the brain and is involved in the intracellular mitogen-activated protein (MAP) signaling and in regulating immune response ( 26 ). The protein coded by gene PPM1A (Protein phosphatase 1A magnesium-dependent, alpha isoform) belongs to the PP2C group of serine–threonine phosphatases. This family of proteins is subclassified into three distinct subptypes, PPM, PPP, and FCP/SCP ( 27 ), that regulate cell proliferation. Of relevance to the phenotype of depression is the PPM1A downregulatory action on cell stress-response pathways ( 28 ). PPM1A is an oligomeric holoenzyme known to modulate the action of the MAP kinases. By modulating the MAP kinases, PPM1A inhibits the activation of p38 and JNK kinase in response to environmental stressors ( 29 ). Further work is necessary to explore the role of PPM1A in depression-relevant processes and how this can be affected by the DNA sequence variation that appears to affect antidepressant response in humans. Three transcripts are known in the PPM1A gene in human; however, only one is currently documented in mouse ( Figure 2 ). it is not known whether similar differentially regulated alternative transcripts of PPM1A may exist in mouse ( 30 ). Another marker that showed a concordant result in mouse and humans lies in the SLC39A14 . Although it did not survive correction for multiple comparisons, this result may also be noteworthy. SLC39A14 encodes the zinc transporter ( 31 ). Hypozincemia may mediate inflammatory processes ( 32 ) and impaired neurogenesis in depression and may be reversible with antidepressant treatment ( 33,34 ). These findings increase the likelihood of a true pharmacogenetic association between SLC39A14 and antidepressant response. This study uses a parallel animal experiment to overcome two major limitations of human pharmacogenetics. First, accessibility of brain tissue in the animal model allows the study of gene expression in a functionally relevant tissue in response to the same antidepressants that are used in humans. Second, prioritization of genes based on mouse expression data facilitates a hypothesis-free search for genetic variants in the context of limited statistical power that currently available samples have for genome-wide testing. A limitation of the current approach lies in the approximate relationship between behaviors observed in animal models and the subjectively experienced symptoms of depression in humans. In addition, our study is limited to one brain region with known relevance to antidepressant action and to four mouse strains with established differences in depression-like behaviors and response to antidepressants. Although the assumptions that the influence of genetic variants on drug action is mediated by differential gene expression is consistent with current knowledge, expression changes in brain regions other than hippocampus and genetic variations that do not sufficiently differ between the four mouse strains would have escaped the current investigation. Finally, it should be noted that although 144 animals is a relatively large sample for a microarray experiment, the power for detecting a strain-by-drug interaction is limited, and the results may be subject to measurement error. In conclusion, in parallel animal and human studies, we found convergent evidence for the involvement of PPM1A in the therapeutic action of noradrenergic antidepressant. If replicated, this finding may be exploited in the search for novel drug targets and in the prediction of differential response for personalized prescribing. The Genome-Based Therapeutic Drugs for Depression study was funded by a European Commission Framework 6 grant , EC Contract Ref: LSHB-CT-2003–503428. Lundbeck provided both nortriptyline and escitalopram free of charge. The Biomedical Research Centre for Mental Health at the Institute of Psychiatry, King's College London and South London , and Maudsley National Health Service Foundation Trust (funded by the National Institute for Health Research, Department of Health, United Kingdom) and GlaxoSmithKline contributed by funding add-on projects at the London Centre. NH has participated in clinical trials sponsored by pharmaceutical companies, including GlaxoSmithKline and Lundbeck. AF, PM, and KA have received consultancy fees and honoraria for participating in expert panels from pharmaceutical companies, including Lundbeck and GlaxoSmithKline. DS has received fees and honoraria for participating in expert panels from pharmaceutical companies, including Lundbeck, Janssen Cilag, GlaxoSmithKline, Eli Lilly, BMS, and AstraZeneca. All other authors report no biomedical financial interests or potential conflicts of interest.
ASJC Scopus Subject Areas
- Biological Psychiatry